tbuckley/cabot-search huggingface dataset:
OS02.6.A Lacosamide in monotherapy in brain tumour-related epilepsy (BTRE): results from an Italian multicentre retrospective study
Authors: F Bruno, F Mo, S Meletti, V Belcastro, S Quadri, M Napolitano, L Bello, F Dainese, M Scarpelli, I Florindo, A Mascia, G Pauletto, A Pellerino, G Giovannini, M Polosa, M Sessa, M Conti Nibali, G Di Gennaro, G Gigli, F Cavallieri, A Pisanello, R Rudà
Journal: Neuro-Oncology (2022)

Abstract Background Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥4 years. Previous studies have reported an efficacy of LCM as add-on treatment in brain tumour-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicentre national cohort of primary brain tumour patients. Patients and Methods Adult patients who were treated with LCM in monotherapy were collected from 12 Italian Centres (either mainly involved in neuro-oncology or in epileptology). Main inclusion criteria were diagnosis of primary brain tumour; at least two focal-onset seizures in the disease course; LCM used either as primary or secondary monotherapy after withdrawal of previous ASMs. For each patient, we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). Results We collected 132 patients. The majority of patients had a diagnosis of diffuse gliomas, being those with lower-grade glioma 66 (50.0%) and those with glioblastoma 33 (25.0%). Overall, LCM led to seizure-freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice.In 14 patients, we observed seizure control despite tumour progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis and use of steroids were significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to the CTCAE classification), and the drop-out rate was low (1.5%). The main side effects were dizziness and somnolence. Conclusion This is the first study on the role of LCM in monotherapy in BTRE. The study has shown a good efficacy and tolerability of LCM with more than a half of patients becoming seizure-free at 6 months and with a very low rate of drop-out. Further studies are needed to confirm these preliminary data in a prospective manner, adding quality of life and neurocognitive functions as endpoints.
P01.10.B The relation between executive functioning and MEG multilayer network centrality in glioma patients
Authors: M R van Lingen, L C Breedt, A Hillebrand, M Klein, M C M Kouwenhoven, J C Reijneveld, P C De Witt Hamer, M L M Zimmermann, F A N Santos, L Douw
Journal: Neuro-Oncology (2022)

Abstract Background Many patients with glioma suffer from deficits in executive functioning (EF), regardless of tumor location and size. While some patients experience improving EF after tumor resection, others deteriorate over time. This variability in cognitive trajectories is still poorly understood, but neuroscientific approaches that view the brain as a network may bear correlative and predictive value in this respect. Particularly integrative network connectivity of the fronto-parietal network are crucial for EF, but studies so far have only investigated isolated neural frequency bands of interest. Here, we synergize fronto-parietal network connectivity across frequency bands and test its explanatory power for EF at diagnosis and 1 year after tumor resection. Material and Methods Patients with diffuse glioma (n=37) underwent neuropsychological assessments, including three tests for EF, and resting-state magnetoencephalography (MEG) at both time points. Patients’ EF performance was standardized to z-scores using validated norm scores, adjusting for age, sex and education. MEG was source-reconstructed using patients’ MRI in combination with a beamformer approach and time series were filtered into six classical frequency bands. Band-specific functional connectivity between 78 cortical regions was estimated, after which an interconnected multilayer, multi-frequency network was created per patient. Multilayer centrality was then calculated as a measure of integrative network connectivity per region, and averaged over all fronto-parietal network regions to yield a single value reflecting integrative, multi-frequency network connectivity per patient at each time point. Results At diagnosis, eight patients had z-scores &amp;lt;-1.5, indicating clinically relevant cognitive deficits. Preoperatively, poorer performance on the Concept Shifting Task was associated with lower multilayer centrality (p=.017), while improving performance on this task from diagnosis to 1 year after resection was associated with an increase in multilayer centrality (p=.022). Multilayer centrality at diagnosis did not significantly predict EF at follow-up. Conclusion Our results establish a significant relationship between poorer and decreasing EF with lower and decreasing multilayer, multi-frequency integrative connectivity of the fronto-parietal network in glioma patients. Studies with larger and more homogeneous samples may further explore the relevance of this multilayer approach in understanding and particularly predicting postoperative decline in EF in these patients, as our sample was characterized by large heterogeneity in cognitively relevant patient and tumor characteristics.
OS09.6.A Factors predicting mood disorders, health related quality of life and sexual disturbances in adults with glioma: a retrospective study
Authors: A Leonetti, G Puglisi, M Rossi, M Conti Nibali, T Sciortino, L Gay, L Vigano', L Fornia, G Cerri, L Bello
Journal: Neuro-Oncology (2022)

Abstract Background It is not clear whether Mood Disorders (MD) and poor Health Related Quality of Life (HRQoL) in glioma patients correlate with clinical and histomolecular features of the tumor or with secondary symptoms associated with treatment. This study assessed the prevalence of MD and decline in HRQoL (with a specific interest in sexuality) in glioma patients, identifying the clinical, imaging and treatment factors associated with these variables. Material and Methods 260 glioma patients (190 lower grade) were evaluated. Patients were prospectively followed-up from admission to 12 months after surgery, for MD and HRQoL assessment. 115 were asked to fill a questionnaire for sexual life investigation. Clinical, imaging, histomolecular features as well as cognitive functions were evaluated. Variables associated with MD,low HRQoL and sexual life impairment were identified by bivariate analysis. Results Factors associated with MD and low HRQoL were different in LGGs and HGGs over the course of the disease. In LGGs the effect of adjuvant treatments was prominent in determining the prevalence of MD and poor HRQoL from the third month after surgery onward. In HGGs, MD and poor HRQoL were associated with older age. In both, cognitive deficits were associated with MD. 42% of patients showed dissatisfaction for their sexual life and decrease of sexual intercourses, which were linked to a reduction of libido (22%), astenia (39%), pharmacological therapy (23%), and self-image insecurity(22%). Patients undergoing adjuvant treatments showed a lower sexual satisfaction. Conclusion Overall the data suggest that worsened quality of life, Incidence of Mood disorder and worsening in sexual life affect a relevant amount of patients affected by glioma. Lack of recovery from functional deficits (language, attentive/executive and motor deficits) and adjuvant therapies (expecially radiotherapy) play a crucial role in determining the emergence of Mood Disorders, low HRQoL and worsened sexual life.
PL02.3.A Survival and T-cell tumor reactivity in patients treated with nivolumab and bevacizumab for recurrent glioblastoma in the clinical trial CA209-9UP
Authors: S Maarup, S Skadborg, A Draghi, A Borch, B Hasselbalch, C Yde, I Svane, S Hadrup, I Christensen, I Law, J Skjoeth-Rasmussen, D Scheie, H Skovgaard Poulsen, U Lassen
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 14.6 months. We have no standard treatment for relapse and current treatment options have limited effect. Novel treatments are necessary to improve survival and quality of life. Material and Methods We present data from; a phase II open label, two-armed clinical trial studying nivolumab and bevacizumab in treatment of recurrent GBM, with progression after Stupp’s regime. Patients were included in two arms depending on the possibility of salvage neurosurgical resection. All patients had biopsies for genome sequencing at primary tumor and recurrence. Both arms received nivolumab and bevacizumab administrated every second week and the surgical arm also received neoadjuvant nivolumab 7 days prior to surgery. Fresh tissue samples were collected for tumor digest, TILs (tumor infiltrating lymphocytes) for phenotype exploration and intracellular staining to test reactivity. Patients were treated until progression, death, or intolerable side effects. Toxicity screens were reported, and follow-up ended in Marts 2022. Results Forty-four patients were included from November 2018 to January 2022; 20 in each arm (four screen-failures). Treatment was overall well tolerated. Median (m) age at inclusion was 57,5 years (arm A) and 50,5 years (arm B), and the groups had an even distribution. The surgical and non-surgical arm had an mPFS of 5.95 and 3.83 months respectively, while the mOS was 13.96 months and 6.77 months, respectively. Multivariate analysis was performed by variables such us steroid, MGMT, gender, age at diagnosis, resection extent and arm. Steroid at inclusion was a significant negative predictor of outcome (p = 0.0378). Controls from our GBM registry (N=140), which were treated with neurosurgical resection and then bevazicumab and irinotecan in recurrent setting had an mOS of 8.64 months (log-rank p=0.0181).Furthermore, reactive tumor infiltrating lymphocytes (TIL) were detected in four of the patients who presented with a longer mOS and mPFS of 16.75 months and 9.18 months, while the 16 patients without TIL reactivity had mOS and mPFS of 12.63 months and 5.13 months, respectively (not significant). Conclusion We found an increased mOS in patients treated with nivolumab and bevacizumab at recurrence, compared to our controls: 13.96 months and 8.64 months, respectively. Four patients with T-cell reactivity towards tumor cells showed an even longer mPFS and mOS. Though not significant, these results warrant further research evaluation in larger patient cohorts. We are currently investigating proteomics and sequencing data to identify predictive biomarkers.
OS06.6.A Real-World Pattern of Care Study on Glioblastoma in the Austrian Population. Final results from 2014-2020
Authors: S Oberndorfer, A Woehrer, M Borkovec, C Marosi, F Payer, T Urbanic-Purkart, M Nowosielski, S Iglseder, G Stockhammer, W Kleindienst, C Florea, A Hager, A Tinchon, M Stultschnig, B Surboeck, J Pichler, A Leibetseder, S Weiss, M Hutterer, L Seebrecht, T Roetzer, A Hainfellner, J Hainfellner
Journal: Neuro-Oncology (2022)

Abstract Background The Austrian ABTR-SANO Glioblastoma Registry is the first population-based assessment of patterns of care for patients with Glioblastoma across Austrian healthcare institutions. The primary aim is to assess the real world effectiveness of administered therapies. Material and Methods Clinical data are collected via a common web-based IT platform “ABTR-SANO Net” since 2014. The database and the ongoing evaluation of clinical parameters, as well as interims analysis are provided in cooperation with a review board. First Outcome analysis, including patients from 2014-2020, was performed at the end of 2021. Results Eleven centers across Austria are involved, and the data of 1416 patients (m/f ratio: 1,35, median age: 66 years) were recently analyzed in detail. Age, extent of resection, as well as ECOG was associated with improved survival. Methylated MGMT Status also showed a moderate survival benefit. Patients with re-resection and re-radiation also exhibited improved survival, which however may be attributed to a selection bias.Second line treatment manly comprised of antiangiogenic treatment, followed by alkylated agents, re-radiation and re-surgery. Median overall survival of all patients was 344 days and clearly age dependent (best for &amp;lt;50 years, worse for&amp;gt;80 years). Conclusion This is the first population based outcome analysis of Glioblastoma in Austria. Results regarding prognostic markers and outcome are mostly comparable with international data. Robust population based data are important in order to monitor quality of health care, and to match the data with results from clinical studies.
KS01.5.A Impact of reduced treatment volumes on pattern of tumor recurrence and radiation dose to normal brain parenchyma in glioblastoma
Authors: G Minniti, M Giraffa, L Capone, G Raza, I Russo, P Navarria, P Tini, A Romano, A Bozzao, S Paolini, V Esposito
Journal: Neuro-Oncology (2022)

Abstract Background to analyze GBM recurrence pattern after standard chemoradiotherapy according to different target volume delineations. We hypothesized that reduced target volume margins may result in similar pattern of failure. Material and Methods 207 patients with GBM who recurred after standard chemoradiation were evaluated. According to the Advisory Committee for Radiation Oncology Practice (ACROP) committee of the European Organisation for Research and Treatment of Cancer (EORTC) target volume delineation guideline, the clinical target volume (CTV) used for treatment planning consisted of residual tumor and resection cavity plus 2-cm margin. MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. The recurrent lesions were defined as in-field, marginal, or distant if &amp;gt;80%, 20-80%, or &amp;lt;20% of the intersecting volume was included in the 95% isodose line. For each patient a theoretical plan consisting of a reduced CTV using 1-cm margin was created and patterns of failure evaluated. Results The median overall survival and progression-free survival were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180 patients, marginal in 5 patients, and distant in 22 patients. Analysis of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred in-field and distant in 75.6% and 18.6% of methylated patients and in 91.8% and 6% of unmethylated patients, respectively (p=0.0046). Patterns of failure were similar between the different treatment plans. Reduced target volumes were associated with significantly lower doses of 20-50 Gy to normal brain and hippocampi (p=0.0001). Conclusion Most of patients treated with standard chemioradiotherapy have in-field recurrences; however, an increased risk of distant recurrences occurs in methylated tumors. The use of target delineation using 1-cm CTV margin is associated with smaller volumes of normal brain and hippocampi irradiated to high doses, without significant changes in the pattern of failure. The impact of different target delineation in terms of efficacy and risk of late radiation-induced toxicity should be assessed prospectively.
P04.02.A Integrated diagnosis and therapeutic decision of pediatric nervous system tumors using a comprehensive genomic profiling test
Authors: A Azevedo, R Roque, J Passos, S Nunes, J Migueis, C Faria, A Sagarribay, A Serpa, L Roque, M Mafra, D Salgado
Journal: Neuro-Oncology (2022)

Abstract Background Nervous system tumors (NST) are one of the leading causes of cancer-related death in children. Next-generation sequencing has enabled the identification of an increasing number of genetic markers, allowing for a more accurate diagnosis, and may help guide clinicians towards a more specific therapeutic approach. Material and Methods Retrospective cohort study of pediatric and young adult patients with NST analyzed with FoundationOneHeme® (FOH) panel from March 2020 to April 2021. This panel was requested, in addition to previously performed pathological reviews and routine genetic tests, in order to obtain more accurate diagnoses and/or possible therapeutic targets. Results Fifty NST were analyzed with FOH panel, corresponding to 49 patients. Median age at NST diagnosis was 13 years (range 0-23 years); 50% were females. Initial diagnoses were: 10 pilocytic astrocytomas, 10 diffuse gliomas, 5 ependymomas, 6 mixed neuronal-glial tumors, 7 embryonal tumors, 3 meningeal tumors, 5 peripheral nervous system tumors (PNST) and 4 other types of tumors. There was a change in the final integrated diagnosis after performing the FOH panel in 10 patients (1 pilocytic astrocytoma, 3 diffuse gliomas, 4 mixed neuronal-glial tumors and 1 PNST). In thirty patients, at least one possible therapeutic target was identified: in 5 patients the target therapies are approved for the patients’ tumor type; in 20 patients, target therapies are approved for the same mutations in other tumor types; and in 30 patients target therapies are still being evaluated in ongoing clinical trials. After the results of the FOH panel were known, the previous therapeutic approach was changed in 15 patients, but in only 4 this was attributed to the new genomic findings. Conclusion Comprehensive genomic profiling tests can improve diagnostic accuracy and allow for a more reliable approach to the management of pediatric patients with nervous system tumors. Although in most patients there was no immediate therapeutic application of the potential targets found, the genomic data obtained could be very useful to patients who may have tumor progressions in the future.
P06.05.A Repeated intracranial administration of ipilimumab and nivolumab in patients with recurrent glioblastoma (rGB): A multi-cohort adaptive phase I clinical trial
Authors: W Geens, J K Schwarze, G Awada, J Tijtgat, L Lescrauwet, X Geeraerts, F Vaeyens, L Cras, A Van Binst, H Everaert, A Michotte, T Cauwenbergh, M Bruneau, R Forsyth, S Tuyaerts, B Neyns, J Duerinck
Journal: Neuro-Oncology (2022)

Abstract Background Perioperative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with IV NIVO was shown to be feasible, safe and associated with an encouraging survival benefit (Duerinck et al. JITC 2021). In subsequent cohorts, combination of iCE administration with biweekly intracavitary (iCA, via an Ommaya reservoir) administration of increasing doses of IPI and NIVO was investigated. Methods Three cohorts were defined according to resectability and postoperative treatment schedule. Patients (pts) in cohort-A and -C underwent a maximal safe resection, pts in cohort-B stereotactic biopsy only. All pts received iCE administration of 10 mg NIVO and 5 mg IPI at the end of the surgical intervention, after which an OR was implanted and an additional 10mg of NIVO and IPI (1, 5 or 10 mg) was administered iCA in cohort-C. All pts received biweekly postoperative NIVO 10 mg IV and iCA administrations of NIVO (3 dose levels were investigated in cohorts-A and -B: 1, 5, or 10 mg) for up to a maximum of 24w postoperatively. In cohort-C, 10 mg of NIVO was complemented with IPI (1, 5, or 10 mg). NGS and RNA gene expression profiling was performed on all tissue samples. Results In total, 44 pts were included (A: n= 16, B: n= 16, C: n= 12 recruitment ongoing). All pts in cohort-A and -B are off study treatment. All pts received the predefined dose of iCE IPI/NIVO and at least one administration of the predefined iCA dose. AE were infrequent and mostly not immune-related. Most common AE were fatigue(n=37), headache(n=25), confusion(n=18) and postoperative fever(n=15). Bacterial colonization of the Ommaya port occurred in 6 pts, subacute neurological deterioration requiring corticosteroids in 8 pts. There were no grade 5 AEs. Median PFS was 13w for cohort-A, 5w in cohort-B and 13w in cohort-C. Median OS is 43weeks in A, 29w in B and is not yet reached in cohort-C after median follow-up of 23w. OS did not differ significantly between study cohorts. OS of pts who underwent surgical resection (cohorts-A and -C) compared favorably to a historical cohort of 469 Belgian patients with rGB (treated in three prospective phase II clinical trials and a large multicenter early acces program for bevacizumab). Conclusions iCE followed by repeated iCA administrations of increasing doses of NIVO with/without IPI in rGB is feasible and safe without dose limiting AEs. A potential survival benefit seems restricted to pts amenable to surgical resection.
OS08.7.A Lomustine and the immunocytokine L19TNF are a promising treatment combination for recurrent glioblastoma
Authors: T Look, E Puca, R Stucchi, R Luca, P Roth, D Neri, M Weller, T Hemmerle, T Weiss
Journal: Neuro-Oncology (2022)

Abstract Background Treatment options for recurrent glioblastoma are limited and with the possible exception of regorafenib, no agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigated different treatment combinations based on the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and translated the most effective treatment combination to patients with recurrent glioblastoma. Material and Methods Orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity of L19TNF in combination with anti-PD1, bevacizumab or lomustine. Tumor growth was monitored by MRI. Flow cytometry and microscopy were used to characterize tumor-infiltrating-immune cells. MHC immunoaffinity purification and mass spectrometry were used to characterize the MHC immunopeptidome. Genetic mouse models were used to study immune-dependent effects. Subsequently, we translated the most efficient treatment combination to patients with recurrent glioblastoma within a phase I/II clinical trial (NCT04573192). Results The combination of L19TNF and lomustine demonstrated strong synergistic anti-tumor activity in two immunocompetent orthotopic glioma models and cured a majority of tumor-bearing mice. In contrast, combinations with anti-PD-1 or bevacizumab had only limited anti-glioma activity. Furthermore, compared to the monotherapies, the combination of L19TNF and lomustine led to the strongest increase in tumor-infiltrating lymphoid cells as demonstrated by flow cytometry and microsopy and to the highest number of peptides presented in the context of MHC-I. The treatment effect was abrograted in different genetic immunodeficient mouse models. The treatment combination of L19TNF and lomustine was well tolerated in the first patients treated within a phase I/II clinical trial and we observed partial tumor responses also in patients with an unmethylated MGMT promoter. Conclusion The combination of L19TNF and lomustine demonstrated promising anti-glioma activity and patients are currently recruited within a phase I/II clinical trial for patients with recurrent glioblastoma.